Abstract
Erythropoietin (EPO)/erythropoietin receptor (EPOR) signaling is involved in the development and regeneration of several non-hematopoietic tissues including the skeleton. EPO is identified as a downstream target of the hypoxia inducible factor-α (HIF-α) pathway. It is shown that EPO exerts a positive role in bone repair, however, the underlying cellular and molecular mechanisms remain unclear. In the present study we show that EPO and EPOR are expressed in the proliferating, pre-hypertrophic and hypertrophic zone of the developing mouse growth plates as well as in the cartilaginous callus of the healing bone. The proliferation rate of chondrocytes is increased under EPO treatment, while this effect is decreased following siRNA mediated knockdown of EPOR in chondrocytes. EPO treatment increases biosynthesis of proteoglycan, accompanied by up-regulation of chondrogenic marker genes including SOX9, SOX5, SOX6, collagen type 2, and aggrecan. The effects are inhibited by knockdown of EPOR. Blockage of the endogenous EPO in chondrocytes also impaired the chondrogenic differentiation. In addition, EPO promotes metatarsal endothelial sprouting in vitro. This coincides with the in vivo data that local delivery of EPO increases vascularity at the mid-stage of bone healing (day 14). In a mouse femoral fracture model, EPO promotes cartilaginous callus formation at days 7 and 14, and enhances bone healing at day 28 indexed by improved X-ray score and micro-CT analysis of microstructure of new bone regenerates, which results in improved biomechanical properties. Our results indicate that EPO enhances chondrogenic and angiogenic responses during bone repair. EPO's function on chondrocyte proliferation and differentiation is at least partially mediated by its receptor EPOR. EPO may serve as a therapeutic agent to facilitate skeletal regeneration.
Highlights
Impaired bone regeneration following injury or under pathological conditions causes severe pain to the patients and considerable financial burden to the society [1,2]
We examined the localization of EPO and erythropoietin receptor (EPOR) in the cartilaginous callus in the middle stage of bone healing
It showed that Both EPO and EPOR were localized in the proliferating, pre-hypertrophic and hypertrophic chondrocytes of the cartilaginous callus (Fig. 1C)
Summary
Impaired bone regeneration following injury or under pathological conditions causes severe pain to the patients and considerable financial burden to the society [1,2]. These conditions include delayed fracture union or non-union, osteoporotic fracture healing, impaired bone repair associated with diabetes, and large bone defects caused by trauma or surgical treatments [3,4,5,6]. The regeneration process has generally been characterized by four steps including inflammation phase with hematoma, cartilage callus formation, bony callus formation and bone remodeling [13,14]. Angiogenesis is essential and depends on hypoxic stimuli and production of proangiogenic factors such as vascular endothelial growth factor (VEGF) [7], Erythropoietin (EPO) [15], fibroblast growth factor (FGF) [16], transforming growth factor-beta (TGFbeta) [17] and insulin like growth factor (IGF-1) [18]
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